Well-known metabolic changes consequent to major injury reflect measurable differences integrated over the whole body. Very little direct information is known about individual organ and tissue contributions to these changes at the whole body level. There is a twofold increase in energy expenditure, a 70% increase in the glucose flux, and a 116% increase in free fatty acid flux. Even with state-of-the-art nutritional therapy in these patients, protein degradation exceeds synthesis by 1.3 g/kg/day. It is becoming clear that specific anabolic agents and/or a more effective balance of substrates or the replacement of missing substrates will be necessary to correct this latter finding but more detailed metabolic information will be necessary to design these newer therapies. During the past several years using PET methods, we have developed and validated methods for measuring: blood flow, blood volume, oxygen extraction, oxygen and glucose utilization in tissues, blood flow and oxygen utilization in the liver, and protein synthesis rates in skeletal muscle. Using these new methods and more standard techniques, the hypotheses evaluated in this project address tissue-specific energy and protein synthesis regulation in animals and in patients and are the following: (I) there are tissue- specific energy requirements which include skeletal muscle that are at or below normal levels and for the liver and heart, these energy requirements are two to three-fold or more above normal; (ii) glucose is taken up into skeletal muscle at or below normal rates and undergoing anaerobic glycolysis to produce lactate, alanine, and little energy; (iii) protein synthesis is at or below normal levels in peripheral muscle and these rates can be modified by anabolic factors. To address these hypotheses, we will measure (1) glucose and fatty acid metabolism in skeletal muscle and other organs in rabbits using PET. To obtain a better understanding of the relationship between the PET measurements of glucose and fatty acid utilization and substrate oxidation, simultaneous steady-state kinetic studies of the metabolic fates of [U-14C] glucose and [1-14C] palmitate will be made in these burned and control animals; (2) glucose and fatty acid metabolism in healthy volunteers and burn-injured patients with burn injuries exceeding 15% BSA; (3) muscle protein synthesis rate in skeletal muscle in burn-injured patients and healthy volunteers; and (4) muscle protein synthesis rate in skeletal muscle in burn-injured patients and healthy volunteers after treatment with recombinant growth hormone and increased concentrations of insulin 1200 mol/L.